Number Of Gadolinium-enhancing Lesions Research Articles

Early imaging predictors of long-term outcomes in relapse-onset multiple sclerosis.

The clinical course of relapse-onset multiple sclerosis is highly variable. Demographic factors, clinical features and global brain T2 lesion load have limited value in counselling individual patients. We investigated early MRI predictors of key long-term outcomes including secondary progressive multiple sclerosis, physical disability and cognitive performance, 15 years after a clinically isolated syndrome. A cohort of patients with clinically isolated syndrome (n = 178) was prospectively recruited within 3 months of clinical disease onset and studied with MRI scans of the brain and spinal cord at study entry (baseline) and after 1 and 3 years. MRI measures at each time point included: supratentorial, infratentorial, spinal cord and gadolinium-enhancing lesion number, brain and spinal cord volumetric measures. The patients were followed-up clinically after ∼15 years to determine disease course, and disability was assessed using the Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test. Multivariable logistic regression and multivariable linear regression models identified independent MRI predictors of secondary progressive multiple sclerosis and Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test, respectively. After 15 years, 166 (93%) patients were assessed clinically: 119 (72%) had multiple sclerosis [94 (57%) relapsing-remitting, 25 (15%) secondary progressive], 45 (27%) remained clinically isolated syndrome and two (1%) developed other disorders. Physical disability was overall low in the multiple sclerosis patients (median Expanded Disability Status Scale 2, range 0-10); 71% were untreated. Baseline gadolinium-enhancing (odds ratio 3.16, P < 0.01) and spinal cord lesions (odds ratio 4.71, P < 0.01) were independently associated with secondary progressive multiple sclerosis at 15 years. When considering 1- and 3-year MRI variables, baseline gadolinium-enhancing lesions remained significant and new spinal cord lesions over time were associated with secondary progressive multiple sclerosis. Baseline gadolinium-enhancing (β = 1.32, P < 0.01) and spinal cord lesions (β = 1.53, P < 0.01) showed a consistent association with Expanded Disability Status Scale at 15 years. Baseline gadolinium-enhancing lesions was also associated with performance on the Paced Auditory Serial Addition Test (β = - 0.79, P < 0.01) and Symbol Digit Modalities Test (β = -0.70, P = 0.02) at 15 years. Our findings suggest that early focal inflammatory disease activity and spinal cord lesions are predictors of very long-term disease outcomes in relapse-onset multiple sclerosis. Established MRI measures, available in routine clinical practice, may be useful in counselling patients with early multiple sclerosis about long-term prognosis, and personalizing treatment plans.

Efficacy of dimethyl fumarate in Japanese multiple sclerosis patients: interim analysis of randomized, double-blind APEX study and its open-label extension.

BackgroundCurrent data for the use of dimethyl fumarate (DMF) in Japanese patients with relapsing–remitting multiple sclerosis (RRMS) is limited.ObjectivesTo assess the efficacy of DMF in Japanese patients with RRMS.MethodsThe phase 3, multinational APEX study (ClinicalTrials.gov identifier: NCT01838668) consisted of two parts: a 24-week double-blind part where subjects were randomized to receive DMF 240 mg or placebo twice daily in East Asian and Eastern European countries, and an open-label extension part where all subjects received DMF. The primary endpoint was the total number of new gadolinium-enhancing lesions in Weeks 12–24. In this interim analysis, we report efficacy data in the Japanese subgroup (DMF n = 56; placebo n = 58) over 72 weeks, including an extension phase.ResultsDMF reduced the total number of new gadolinium-enhancing lesions in Weeks 12–24 by 85% versus placebo (p < 0.0001). At Week 24, the annualized relapse rate was also reduced by 48% with DMF, versus placebo. DMF reduced the probability of relapse from Week 8 and was sustained. The number of gadolinium-enhancing lesions was maintained through 72 weeks.ConclusionsDMF demonstrated sustained efficacy in this Japanese subgroup. The results were consistent with those observed in studies of DMF enrolling primarily Caucasian patients.

Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis

BackgroundBruton’s tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo.MethodsIn this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24. Key secondary end points included the annualized relapse rate and change from baseline in the score on the Expanded Disability Status Scale (EDSS).ResultsA total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P=0.32), 0.30 in the evobrutinib 75-mg once-daily group (P=0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P=0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib.ConclusionsPatients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. (Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.)

A BTK-Inhibitor Reduced Number of Gadolinium-Enhancing Lesions in Multiple Sclerosis

A BTK-Inhibitor Reduced Number of Gadolinium-Enhancing Lesions in Multiple Sclerosis

MRI evidence of acute inflammation in leukocortical lesions of patients with early multiple sclerosis.

To identify gadolinium-enhancing lesions affecting the cortex of patients with early multiple sclerosis (MS) and to describe the frequency and evolution of these lesions. We performed a retrospective, observational, longitudinal analysis of MRI scans collected as part of the Betaseron vs Copaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3T MRI Endpoints (BECOME) study. Seventy-five patients with early-stage MS were scanned monthly, over a period of 12-24 months, using 3T MRI after administration of triple-dose gadolinium. A total of 1,188 scans were included in the analysis. A total of 139 were selected using an image pipeline algorithm that integrated the image information from cortical gray matter masks and gadolinium-enhancing lesion masks. These scans were evaluated to identify gadolinium-enhancing lesions affecting the cortex. The total number of gadolinium-enhancing lesions was 2,044. The number of gadolinium-enhancing lesions affecting the cortex was 120 (6%), 95% of which were leukocortical. The number of patients who showed gadolinium-enhancing lesions affecting the cortex was 27 (36%). The number of gadolinium-enhancing lesions affecting the cortex at baseline was 25 (21%) and the number of new lesions that developed in follow-up scans was 49 (41%). The number of persistent lesions was 46 (38%). The presence of enhancing lesions affecting the cortex and adjacent white matter, although transient and not frequent, suggests that at least some cortical lesions are related to blood-brain barrier disruption. Our data support the concept that there may be an acute inflammatory phase in the development of leukocortical MS lesions. NCT00176592.

Serum neurofilament is associated with progression of brain atrophy and disability in early MS.

To investigate a potential effect of riluzole on serum neurofilaments (Nf) compared to placebo and the relationship between longitudinal clinical and MRI outcomes and serum Nf levels. Serum samples were obtained from participants enrolled in a randomized double-blind trial of neuroprotection with riluzole vs placebo as an add-on to weekly interferon-β (IFN-β)-1a IM initiated 3 months after randomization. Nf measurements were performed by ELISA and electrochemiluminescence immunoassay. Longitudinal serum samples were available from 22 riluzole and 20 placebo participants over 24 months. There was no observed treatment effect with riluzole. Nf light chain (NfL) levels decreased over time (p = 0.007 at 24 months), whereas the Nf heavy chain was unchanged (p = 0.997). Changes in NfL were correlated with EDSS change (p = 0.009) and neuropsychological outcomes. Brain volume decreased more rapidly in patients with high baseline NfL (p = 0.05 at 12 months and p = 0.008 at 24 months) and this relationship became stronger at 24 months (p = 0.024 for interaction). Higher and increasing NfL predicted higher number of gadolinium-enhancing lesions (p < 0.001 for both). Our findings support the potential value of serum NfL as a marker of neuroaxonal injury in early multiple sclerosis. Its reduction over time could represent regression to the mean, or a possible treatment effect of IFN-β-1a. The association with whole brain atrophy and the formation of acute white matter lesions has relevant implications to use serum NfL as a noninvasive biomarker of the overall consequences of brain damage and ongoing disease activity. NCT00501943.

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis

BackgroundB cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells.MethodsIn two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate.ResultsThe annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a.ConclusionsAmong patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann–La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333, respectively.)

Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results

Background: Open-label 15-month follow-up of the double-blind, placebo-controlled Glatiramer Acetate clinical Trial to assess Equivalence with Copaxone® (GATE) trial. Objective: To evaluate efficacy, safety, and tolerability of prolonged generic glatiramer acetate (GTR) treatment and to evaluate efficacy, safety, and tolerability of switching from brand glatiramer acetate (GA) to GTR treatment. Methods: A total of 729 patients received GTR 20 mg/mL daily. Safety was assessed at months 12, 15, 18, 21, and 24 and Expanded Disability Status Scale and magnetic resonance imaging (MRI) scans at months 12, 18, and 24. The presence of glatiramer anti-drug antibodies (ADAs) was tested at baseline and months 1, 3, 6, 9, 12, 18, and 24. Results: The mean number of gadolinium-enhancing lesions in the GTR/GTR and GA/GTR groups was similar at months 12, 18, and 24. The change in other MRI parameters was also similar in the GTR/GTR and GA/GTR groups. The annualized relapse rate (ARR) did not differ between the GTR/GTR and GA/GTR groups, 0.21 and 0.24, respectively. The incidence, spectrum, and severity of reported adverse events did not differ between the GTR/GTR and GA/GTR groups. Glatiramer ADA titers were similar in the GTR/GTR and GA/GTR groups. Conclusion: Efficacy and safety of GTR is maintained over 2 years. Additionally, switching from GA to GTR is safe and well tolerated.

Natalizumab discontinuation is associated with a rebound of cognitive impairment in multiple sclerosis patients.

Natalizumab discontinuation is associated with a disease reactivation in multiple sclerosis (MS) patients. Whether this reactivation involves also cognitive functions is not known to date. To assess the persistence of the effect of natalizumab on cognitive functions 1year after its discontinuation, we compared the longitudinal changes of cognitive performances in two groups of patients. The interrupters, 30 MS patients, have stopped natalizumab due to PML concern, and the continuers, 28 MS patients, continued the treatment. The cognitive impairment index (CII) was used as main outcome measure. As expected, during the natalizumab treatment, we observed a significant reduction of the relapse rate and the number of gadolinium-enhancing lesions along with a reduction of the CII. After 1year of discontinuation, the beneficial effect on cognitive functions was lost in the interrupters group, as the mean CII increased in comparison with the mean at the end of natalizumab treatment (12.2±7.9 vs 9.3±8.1, p<0.0001). As opposite, in the continuers group, the CII further decreased after an additional year of treatment (8.4±5.1 vs 9.8±4.6, p=0.007). A multivariate logistic regression model revealed as predictors of cognitive worsening male sex, disease duration, and the treatment discontinuation. The worsening of cognitive functions after natalizumab discontinuation goes in parallel with the clinical/radiological disease reactivation. Our data reinforce the hypothesis that, in the short-term, natalizumab exerts its positive impact on cognitive functions by means of its anti-inflammatory properties.

Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial

Modulation of sphingosine 1-phosphate (S1P) receptors in a non-selective manner decreases disease activity in patients with multiple sclerosis but has potential safety concerns. We assessed the safety and efficacy of the oral selective S1P receptor modulator ozanimod in patients with relapsing multiple sclerosis. RADIANCE is a combined phase 2/3 trial. Patients with relapsing multiple sclerosis were recruited from 55 academic and private multiple sclerosis clinics in 13 countries across Europe and the USA. Eligible participants were aged 18-55 years, had an Expanded Disability Status Scale (EDSS) score of 0-5·0, and had either one or more relapses in the previous 12 months, or one or more relapses in the past 24 months and one or more gadolinium-enhancing lesions on MRI in the previous 12 months before screening. Participants were assigned by a computer-generated randomisation sequence in a 1:1:1 ratio to ozanimod (0·5 mg or 1 mg) or matching placebo once daily for 24 weeks by an independent, unmasked, statistical team. Trial participants, study site personnel, MRI assessors, steering committee members, and the study statistician were masked to treatment assignment. To attenuate first-dose cardiac effects, ozanimod was up-titrated from 0·25 mg to 0·5 mg or 1 mg over 8 days. The primary endpoint was the cumulative number of total gadolinium-enhancing MRI lesions measured by an independent MRI analysis centre at weeks 12-24 after treatment initiation. Analysis was by intention to treat. Here, we report results from the 24-week phase 2 trial. This trial is registered with ClinicalTrials.gov, number NCT01628393. The 2-year phase 3 trial is ongoing. The first patient was randomised on Oct 18, 2012, and the final visit of the last randomised patient was on May 11, 2014. The intention-to-treat and safety population consisted of 258 participants, 88 were assigned placebo, 87 ozanimod 0·5 mg, and 83 ozanimod 1 mg; 252 (98%) patients completed the assigned treatment. The mean cumulative number of gadolinium-enhancing lesions at weeks 12-24 was 11·1 (SD 29·9) with placebo compared with 1·5 (3·7) with ozanimod 0·5 mg (odds ratio 0·16, 95% CI 0·08-0·30; p<0·0001) and 1·5 (3·4) with ozanimod 1 mg (odds ratio 0·11, 95% CI 0·06-0·21; p<0·0001). Three serious adverse events unrelated to treatment were reported in patients assigned ozanimod 0·5 mg: optic neuritis, somatoform autonomic dysfunction, and cervical squamous metaplasia (HPV-related). No serious infectious or cardiac adverse events were reported, and no cases of macular oedema arose. The most common adverse events in the ozanimod 0·5 mg and 1 mg groups compared with placebo were nasopharyngitis (11 and five vs 12), headache (five and three vs eight), and urinary-tract infections (six and two vs two). The maximum reduction in mean heart rate by Holter monitoring during the first 6 h in ozanimod-treated participants was less than 2 beats per min (bpm) compared with baseline, with no patient having a minimum hourly heart rate less than 45 bpm. Electrocardiograms and 24-h Holter monitoring showed no increased incidence of atrioventricular block or sinus pause with ozanimod. Ozanimod significantly reduced MRI lesion activity in participants with relapsing multiple sclerosis, with a favourable safety profile over a period of 24 weeks. These findings warrant phase 3 trials, which are ongoing. Receptos, Inc.

Эффективность митоксантрона у больных с прогредиентными типами течения рассеянного склероза

Изучена эффективность, безопасность и переносимость митоксантрона у 67 пациентов с прогредиентными типами течения (ПТТ) рассеянного склероза (РС).Проведен анализ клинико-радиологических данных у 19 больных с первично-прогредиентным (ППТ) и у 48 больных со вторично-прогредиентным течением (ВПТ) РС, получавших цитостатик II ряда — митоксантрон. Оценка клинической и радиологической активности заболевания по результатам лечения проводилась непосредственно после курса приема митоксантрона и ежегодно в течение 2 лет после его окончания. Учитывалась динамика выраженности неврологического дефицита по данным шкалы инвалидизации EDSS, наличие и длительность этапа стабилизации, темпы и варианты дальнейшего прогрессирования, характер прогноза, количество гадолиний-контрастированных повреждений по данным МРТ. С учетом этих показателей были разработаны критерии высокой, умеренной и низкой эффективности лечения. К моменту окончания курса митоксантрона высокая эффективность лечения в виде частичного регресса неврологического дефицита на фоне стабилизации была получена у 25 % больных при ВПТ и у 21,1 % — при ППТ с неопределенным характером прогноза; умеренная эффективность в виде стойкой стабилизации также преобладала у больных с неопределенным характером прогноза — у 50 % при ВПТ и у 36,8 % при ППТ; низкая эффективность в виде замедления темпов неуклонного варианта прогрессирования и его трансформации в более благоприятный поступательный вариант определялась у 22,9 % больных с ВПТ и у 26,3 % с ППТ с неблагоприятным характером прогноза. К моменту окончания двухлетнего катамнестического наблюдения позитивный терапевтический эффект митоксантрона с высокой и умеренной эффективностью сохранялся у 50 % больных при ВПТ и у 42,1 % — с умеренной эффективностью при ППТ. За этот период отрицательная динамика с избирательной реорганизацией показателей эффективности была получена у 20 (41,6 %) больных с ВПТ и у 11 (57,9 %) — с ППТ РС. Митоксантрон, по данным мониторинга МРТ, замедляет радиологическую активность воспалительного процесса, уменьшает число новых подтвержденных гадолиний-контрастируемых очагов поражения, но не оказывает влияния на общий нейродегенеративный процесс, который зависит от длительности, тяжести и типа течения РС с преобладанием при ППТ.Заключение. Доказана клиническая и радиологическая эффективность цитостатика митоксантрона в качестве метода деэскалационной иммуносупрессивной терапии при тяжелых малокурабельных прогредиентных формах РС с учетом типа течения, характера прогноза, степени выраженности неврологического дефицита, темпов и вариантов прогрессирования.

Subclinical MRI disease activity influences cognitive performance in MS patients

BackgroundThe pathological mechanisms underlying cognitive dysfunction in multiple sclerosis (MS) are not yet fully understood and, in addition to demyelinating lesions and gray-matter atrophy, subclinical disease activity may play a role. ObjectiveTo evaluate the contribution of asymptomatic gadolinium-enhancing lesions to cognitive dysfunction along with gray-matter damage and callosal atrophy in relapsing-remitting MS (RRMS) patients. MethodsForty-two treated RRMS and 30 controls were evaluated. MRI (3T) variables of interest were brain white-matter and cortical lesion load, cortical and deep gray-matter volumes, corpus callosum volume and presence of gadolinium-enhancing lesions. Outcome variables included EDSS, MS Functional Composite (MSFC) subtests and the Brief Repeatable Battery of Neuropsychological tests. Cognitive dysfunction was classified as deficits in two or more cognitive subtests. Multivariate regression analyses assessed the contribution of MRI metrics to outcomes. ResultsPatients with cognitive impairment (45.2%) had more cortical lesions and lower gray-matter and callosal volumes. Patients with subclinical MRI activity (15%) had worse cognitive performance. Clinical disability on MSFC was mainly associated with putaminal atrophy. The main independent predictors for cognitive deficits were high burden of cortical lesions and number of gadolinium-enhancing lesions. ConclusionsCognitive dysfunction was especially related to high burden of cortical lesions and subclinical disease activity. Cognitive studies in MS should look over subclinical disease activity as a potential contributor to cognitive impairment.

Time course of clinical and neuroradiological effects of delayed-release dimethyl fumarate in multiple sclerosis.

Background and purposeDelayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF), demonstrated efficacy and safety in relapsing−remitting multiple sclerosis in the 2-year, randomized, placebo-controlled, phase 3 DEFINE and CONFIRM trials. A post hoc analysis of integrated data from DEFINE and CONFIRM was conducted to determine the temporal profile of the clinical and neuroradiological effects of DMF.MethodsEligible patients were randomized to receive placebo, DMF 240 mg twice (BID) or three times (TID) daily or glatiramer acetate (GA; reference comparator; CONFIRM only) for up to 96 weeks. Patients in the GA group were excluded from this analysis.ResultsA total of 2301 patients were randomized and received treatment with placebo (n = 771) or DMF BID (n = 769) or TID (n = 761). DMF significantly reduced the annualized relapse rate beginning in weeks 0–12 (BID, P = 0.0159; TID, P = 0.0314); the proportion of patients relapsed beginning at week 10 (BID, P = 0.0427) and week 12 (TID, P = 0.0451); and the proportion of patients with 12-week confirmed disability progression beginning at week 62 (BID, P = 0.0454) and week 72 (TID, P = 0.0399), compared with placebo. These effects were sustained throughout the 2-year study period. DMF significantly reduced the odds of having a higher number of gadolinium-enhancing lesions by 88% (BID) and 75% (TID) and the mean number of new or enlarging T2 lesions by 72% (BID) and 67% (TID), from the first post-baseline magnetic resonance imaging assessment at 24 weeks (all P < 0.0001 versus placebo).ConclusionsIn phase 3 clinical trials, DMF demonstrated rapid and sustained clinical and neuroradiological efficacy in relapsing−remitting multiple sclerosis.

Molecular mechanism underlying the impact of vitamin D on disease activity of MS

ObjectiveSome previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D.MethodsThis study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium-enhancing lesions present on repeated magnetic resonance imaging (MRIs).ResultsThe number of gadolinium-enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems-level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene–gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well-described targets of IFNB-1b and a regulator of sphingosine-1-phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB-1b.InterpretationHere, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN-beta-1b.

Abnormal inflammatory activity returns after natalizumab cessation in multiple sclerosis

ObjectiveTo characterise recurrence of multiple sclerosis (MS) inflammatory activity during the year following natalizumab (NTZ) cessation.MethodsThirty-two patients with MS were included in a monocentric cohort study. Data were collected prospectively...

The effectiveness of dimethyl fumarate monotherapy in the treatment of relapsing-remitting multiple sclerosis: a systematic review and meta-analysis.

Background:Dimethyl fumarate (BG-12, Tecfidera®) is a new oral drug approved by FDA and EMA in March 2013 for relapsing – remitting multiple sclerosis (RRMS). The drug was much anticipated because of its possible superiority over currently available medications: fingolimod and teriflunomide as the only MS treatments currently available in oral form.Objective:The aim of this systematic review with meta-analysis was to assess the efficacy and safety of BG-12 in the treatment of RRMS.Methods:A systematic literature search was conducted in Medline/PubMed, EMBASE, and Cochrane Library up till 3rd November, 2013. We sought all published randomized clinical trials evaluating the use of dimethyl fumarate for the treatment of patients with RRMS. All included studies were critically appraised and analyzed with the use of Review Manager 5.1.0. software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol.Results:Two trials, DEFINE and CONFIRM involved 2 651 patients and compared dimethyl fumarate taken either two or three times daily with placebo in patients with RRMS. Additionally in CONFIRM trial third group of patients received glatiramer acetate. The overall results of the meta-analysis showed that BG-12 (at both dosages) given to patients with RRMS is safe and statistically significantly more effective than placebo in reducing the proportion of patients who had a relapse by 2 years, the rate of disability progression and the mean number of gadolinium-enhancing lesions at 2 years. The comparison between BG-12 and glatiramer acetate revealed that the analyzed agent could potentially be more effective in the treatment of RRMS.Conclusions:Despite limited RCTs data available, both analyzed BG-12 regimens showed their efficacy on clinical disease parameters and other measures of disease activity in RRMS. The safety profile of the study agent was acceptable.

Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial

Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production. In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18-60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosis drugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT). Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (atacicept 25 mg, 0·86, 95% CI 0·43-1·74; 75 mg, 0·79, 0·40-1·58; 150 mg, 0·98, 0·52-1·81; placebo, 0·38, 0·17-0·87). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97-5·27; 75 mg, 2·30, 1·08-4·92; 150 mg, 2·49, 1·18-5·27; placebo, 3·07, 1·40-6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo group Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted. Merck Serono (Merck KGaA) and EMD Serono (Merck KGaA).

Rituximab for relapsing-remitting multiple sclerosis

This is an update of the Cochrane review "Rituximab for relapsing-remitting multiple sclerosis" (first published in The Cochrane Library 2011, Issue 12).More than 80% of individuals with multiple sclerosis (MS) experience a relapsing-remitting disease course. Approximately 10 years after disease onset, an estimated 50% of individuals with relapsing-remitting MS (RRMS) convert to secondary progressive MS. MS causes a major socioeconomic burden for the individual patient and for society. Effective treatment that reduces relapse frequency and prevents progression could impact both costs and quality of life and help to reduce the socioeconomic burden of MS. Alternative and more effective MS treatments with new modes of action and good safety are needed to expand the current treatment repertoire. It has been shown that B lymphocytes are involved in the pathophysiology of MS and rituximab lyses B-cells via complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Current clinical trials are evaluating the role of rituximab as a B-cell depletion therapy in the treatment of RRMS. The safety and effectiveness of rituximab, as monotherapy or combination therapy, versus placebo or approved disease-modifying drugs (DMDs) (interferon-β (IFN-β), glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab) to reduce disease activity for people with RRMS were assessed. The Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (9 August 2013). We checked the references in identified trials and manually searched the reports (2004 to August 2013) from neurological associations and MS societies in Europe and America. We also communicated with researchers who were participating in trials on rituximab and contacted Genentech, BiogenIdec and Roche. All randomised, double-blind, controlled parallel group clinical trials with a length of follow-up equal to or greater than one year evaluating rituximab, as monotherapy or combination therapy, versus placebo or approved DMDs for patients with RRMS without restrictions regarding dosage, administration frequency and duration of treatment. We used the standard methodological procedures of The Cochrane Collaboration. Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among the review authors. Principal investigators of included studies were contacted for additional data or confirmation of data. One trial involving 104 adult RRMS patients with an entry score ≤ 5.0 on the Expanded Disability Status Scale (EDSS) and at least one relapse during the preceding year was included. This trial evaluated rituximab as monotherapy versus placebo, with a single course of 1000 mg intravenous rituximab (on day 1 and day 15). A significant attrition bias was found at week 48 (24.0%). Patients receiving rituximab had a significant reduction in total number of gadolinium-enhancing lesions at week 24 (mean number 0.5 versus 5.5; relative reduction 91%) and in annualised rate of relapse at week 24 (0.37 versus 0.84) but not at week 48 (0.37 versus 0.72). Disability progression was not included as an outcome in this trial. More patients in the rituximab group had adverse events within the 24 hours after the first infusion (78.3% versus 40.0%), such as chills, headache, nausea, pyrexia, pruritus, fatigue, throat irritation, pharyngolaryngeal pain, and most were mild-to-moderate events (92.6%). The most common infection-associated adverse events (> 10% in the rituximab group) were nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. Among them, only urinary tract infections (14.5% versus 8.6%) and sinusitis (13.0% versus 8.6%) were more common in the rituximab group. One ongoing trial was identified. There is not sufficient evidence to support the use of rituximab as a disease-modifying therapy for RRMS because only one RCT was included. The quality of the study was limited due to high attrition bias, the small number of participants, and short follow-up. The beneficial effects of rituximab for RRMS remain inconclusive. However, short-term treatment with a single course of rituximab was safe for most patients with RRMS. Mild-to-moderate infusion-associated adverse events were common, as well as nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. The potential benefits of rituximab for treating RRMS need to be evaluated in large-scale studies that are of high quality along with long-term safety.

Quantitative MRI analysis in children with multiple sclerosis: a multicenter feasibility pilot study.

BackgroundPediatric multiple sclerosis (MS) is a rare disorder with significant consequences. Quantitative MRI measurements may provide significant insights, however multicenter collaborative studies are needed given the small numbers of subjects. The goal of this study is to demonstrate feasibility and evaluate lesion volume (LV) characteristics in a multicenter cohort of children with MS.MethodsA common MRI-scanning guideline was implemented at six member sites of the U.S. Network of Pediatric MS Centers of Excellence. We included in this study the first ten scans performed at each site on patients meeting the following inclusion criteria: pediatric RRMS within 3 years of disease onset, examination within 1 month of MRI and no steroids 1 month prior to MRI. We quantified T2 number, T2-LV and individual lesion size in a total of 53 MRIs passing quality control procedures and assessed gadolinium-enhancing lesion number and LV in 55 scans. We studied MRI measures according to demographic features including age, race, ethnicity and disability scores, controlling for disease duration and treatment duration using negative binomial regression and linear regression.ResultsThe mean number of T2 lesions was 24.30 ± 19.68 (range:1–113) and mean gadolinium-enhancing lesion count was 1.85 ± 5.84, (range:0–32). Individual lesion size ranged from 14.31 to 55750.60 mm3. Non-white subjects had higher T2–LV (unadjusted pT2-LV = 0.028; adjusted pT2-LV = 0.044), and maximal individual T2-LV (unadjusted pMax = 0.007; adjusted pMax = 0.011) than white patients. We also found a trend toward larger mean lesion size in males than females (p = 0.07).ConclusionAssessment of MRI lesion LV characteristics is feasible in a multicenter cohort of children with MS.

Automated identification of brain new lesions in multiple sclerosis using subtraction images.

To propose and evaluate a new automated method for the identification of new/enlarging multiple sclerosis (MS) lesions on subtracted images (SI). The subtraction of serially acquired images has shown great potential in assessing new/enlarging brain magnetic resonance imaging (MRI) lesions in MS patients. However, this approach relies on the manual definition of lesions, which is labor-intensive and subject to operator-dependent variability. An overestimated mask of candidate SI lesions was created and then these hyperintense voxel clusters were filtered using specific constraints for extent, shape, and intensity. The method was tested on normal and pathological MRI datasets. The automated method did not detect hyperintense voxels on SI of healthy controls. SI lesions were identified manually and automatically in a multicenter MS dataset of 19 patients with paired MRI over 36 weeks. Sensitivity of the method was high (0.91) and in agreement with the results of manually defined SI lesions (Cohen's k=0.82,95% confidence interval [CI]: 0.77–0.87). On a second multicenter MS dataset of 103 patients with paired MRI over 76 weeks, the number of SI lesions detected automatically correlated with the number of gadolinium-enhancing lesions(r=0.74). The proposed method is robust, accurate,and sensitive and may be used with confidence in Phase II MS trials.